It is now well established that the enzyme xanthine oxidase is implicated in the production of uric acid by the body, converting hypoxanthine into xanthine and xanthine, in turn, into uric acid. Under normal conditions, uric acid (2,6,8-trioxypurine) is found in the body in only small amounts, a concentration in the blood on the order of about one to about three micrograms per 100 milliliters. Under certain pathological conditions, however, as for example, gout, the concentration of uric acid increases significantly.
Gout, of course, is a metabolic disturbance in the body resulting from an overproduction of uric acid, chronic hyperuricemia (elevated blood uric acid), and progressive accumulation of uric acid in the tissues. The body may also progressively lose its capacity to excrete uric acid and is, therefore, in a constant state of uric acid imbalance, accumulating a greater and greater excess. Its concentration in the blood is high, and, because of its low solubility, it tends to precipitate and form deposits at various sites where the blood flow is least active, particularly joints and cartilaginous tissues.
One approach to the control of gout commonly used in the past has been the prescription of drugs which tended to prevent the accumulation of uric acid in the body and thus diminish the likelihood of acute recurrences. Such drugs are identified as "uricosuric agents" and promote the excretion of uric acid in the urine. Examples of such drugs include p-dipropylsulfamyl benzoic acid and sulfinpyrazone. These drugs cannot, however, be administered in conjunction with aspirin or any other salicylate, which might be given to relieve pain, because the agents and salicylates are mutually antagonistic, i.e., each tends to offset the action of the other.
A second approach to the treatment of gout which has become popular is the use of the drug allopurinol, ##STR2## which blocks the production of uric acid by the body by inhibiting the enzyme xanthine oxidase, which, as noted previously, is responsible for converting hypoxanthine into xanthine and xanthine into uric acid. While allopurinol is effective to inhibit the enzyme xanthine oxidase, nevertheless there are disadvantages which limit its suitability.
First, its toxicity is higher than desirable, having a lethal dosage level, LD.sub.50 (the dose required to kill 50% of a group of animals in two weeks when injected into the intraparietal cavity) of about 150 milligrams per kilogram of body weight. Moreover, allopurinol is gradually metabolized in vivo to 4,6-dihydroxy pyrazolo[3,4-d]pyrimidine, which is not as effective an inhibitor as is allopurinol. In addition to the foregoing disadvantages, allopurinol, because of its chemical nature, must compete with xanthine to occupy a place on the enzyme xanthine oxidase in order to inhibit the enzyme and thus prevent the formation of uric acid by the body, which likewise limits its efficiency. It is also known that acute attacks of gouty arthritis occur in the early treatment with allopurinol. It is accordingly necessary to give colchicine during the initial period of therapy to prevent such acute attacks. There have also been reports of the development of a pruritic rash in some patients and of the occasional occurrence of drowsiness when allopurinol is administered. In view of the foregoing, it is apparent that xanthine oxidase inhibitors which are of acceptable toxicity and at the same time possess increased inhibition efficiency as compared to allopurinol are highly desirable.
In the application of Darrell E. O'Brien and Roland K. Robins entitled "Xanthine Oxidase Inhibitors", Ser. No. 172,196, assigned to the same assignee as this application, imidazo[1,2,a] and pyrazolo[1,5,a]pyrimidine compounds are disclosed which demonstrate significant inhibitory activity. Certain of such compounds possess greater inhibition against the enzyme xanthine oxidase than does allopurinol. While such compounds are thus effective inhibitors, there is yet the need for inhibitors possessing still increased efficiency.